Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome

Harshit Singh; Vikas Agarwal; Saurabh Chaturvedi; Durga Prasanna Misra; Akhilesh Kumar Jaiswal; Narayan Prasad

doi:10.3389/fphar.2019.00558

Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome

Front Pharmacol. 2019 May 22:10:558. doi: 10.3389/fphar.2019.00558. eCollection 2019.

Authors

Harshit Singh¹, Vikas Agarwal¹, Saurabh Chaturvedi¹, Durga Prasanna Misra¹, Akhilesh Kumar Jaiswal², Narayan Prasad²

Affiliations

¹ Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
² Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.

Abstract

Background: Reduced HDACs levels have been reported in steroid resistant chronic obstructive pulmonary disease and bronchial asthma patients. P-glycoprotein (P-gp) over expression in peripheral blood mononuclear cells (PBMCs) has been reported in patients with steroid resistant nephrotic syndrome (NS). Whether and how HDACs and P-gp are linked with each other is not clear, especially in NS patients. Aim: To evaluate mRNA expression of P-gp/MRP-1 and HDAC2 in PBMCs of steroid sensitive (SSNS) and steroid resistant nephrotic syndrome (SRNS) patients, and determine the relationship between expression of HDAC2 and P-gp/ MRP-1in NS patients. Methods: Twenty subjects (10 in each group), SSNS (mean age 7.54 ± 3.5 years), and SRNS (mean age 8.43 ± 3.8 years) were recruited. mRNA expression of HDAC2 and P-gp/MRP-1 was studied by quantitative real time PCR. PBMCs were treated with Theophylline, 1 μM, and Trichostatin A, 0.8 μM, for 48 h for induction and suppression of HDAC2, respectively. Results: At baseline, expression of P-gp (4.79 ± 0.10 vs. 2.13 ± 0.12, p < 0.0001) and MRP-1 (3.99 ± 0.08 vs. 1.99 ±0.11, p < 0.0001) on PBMCs were increased whereas, HDAC2 mRNA levels (2.97 ± 0.15 vs. 6.02 ± 0.13, p < 0.0001) were significantly decreased in SRNS as compared to that of SSNS patients. Compared to baseline, theophylline reduced mRNA expression of P-gp and MRP-1 (fold change 2.65 and 2.21, ^* p < 0.0001 in SRNS) (fold change 1.25, 1.24, ^* p < 0.0001 in SSNS), respectively. However, it increased the expression of HDAC2 (fold change 5.67, ^* p < 0.0001 in SRNS) (fold change 6.93, ^* p < 0.0001 in SSNS). Compared to baseline, TSA treatment increased mRNA levels of P-gp and MRP-1 (fold change 7.51, 7.31, ^* p < 0.0001 in SRNS) and (fold change 3.49, 3.35, ^* p < 0.0001 in SSNS), respectively. It significantly decreased the level of HDAC2 (fold change 1.50, ^* p < 0.0001 in SRNS) (fold change 2.53, ^* p < 0.0001 in SSNS) patients. Conclusion: Reduced HDAC2 and increased P-gp/MRP-1 activity may play a role in response to steroids in childhood NS. HDAC2 and P-gp/MRP-1 are in reciprocal relationship with each other.

Keywords: HDAC inhibitor and HDAC stimulator; P-glycoprotein (P-gp); histone deacetylase2 (HDAC2); multidrug resistance-associated protein 1 (MRP-1); steroid resistance.